Administration of group A streptococcal cell wall (SCW) peptidoglycan- polysaccharide complexes induces arthritis, liver fibrosis, and spleen cell anergy in genetically susceptible rodents and provides a model to explore all phases of an immune response and the consequences of its dysregulation. One objective of this research is to identify known and novel molecules expressed during the development of inflammation and we have focused on the chemokine superfamily using in vitro, in vivo and ex vivo approaches. Cultured synovial fibroblasts express specific chemokine genes, including CINC and MCP-1, but not others, under pro-arthropathic conditions, implicating selective recruitment of leukocyte populations. Moreover, by engineering mutated forms of CINC and other chemokines with sequence modifications predicted to produce receptor antagonism(RA), it may be possible to block chemotaxis and control leukocyte accumulation at sites of inflammation. To identify additional genes expressed during SCW-induced inflammation, we have used differential display PCR to compare gene expression in granulomatous and normal livers. Several partial cDNAs representing differentially expressed and novel genes have been cloned and sequenced. Continued definition of these experimental pathways may provide insight into human chronic inflammatory disorders including arthritis, injury associated disorders, and periodontitis. For example, our previously demonstrated involvement of the NO pathway in this model is consistent with the elevated nitrite levels we detect in synovial fluids from patients with rheumatoid arthritis and gingival fluids in periodontal disease. By immunohistochemistry, the inflamed human tissue samples have increased numbers of T cells, B cells and macrophages, and positive staining for iNOS protein. Since these data provide evidence for the existence of inducible NO biosynthesis in human inflammatory disease, the use of inhibitors selective for iNOS may be beneficial.